15-Sulfonamidoprostaglandin derivatives

#The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. Their structure, nomenclature, biological activities and medicinal use have been described in U.S. Pat. No. 3,971,825 and U.S. Pat. No. 3,984,400.

#A common problem confronting medical scientists who attempt to make biologically efficacious, synthetic drugs is modulation of the biological action of an appropriate lead compound. A traditional approach seeks an increase in biological potency. The prostaglandin approach, however, is framed around increased oral activity and increased duration of action. In addition, enhancement of one of the diverse physiological effects of the prostaglandin class and diminution of the others are sought so that the synthetic prostaglandins will not exhibit incompatible side effects. For example, it would be clinically inadvisable to administer an antiulcer synthetic prostaglandin that also causes diarrhea.

#To achieve increased selectivity, researchers have concentrated their efforts on the "active" sites of the natural prostaglandins. In the main, these include the C-1 carboxylic acid group, the carboxylic acid side chain, the cyclopentane ring and the lipophilic end of the bottom side chain. Such work is publicized in the following patents: U.S. Pat. No. 4,024,179, U.S. Pat. No. 3,954,741, U.S. Pat. No. 3,987,087, U.S. Pat. No. 3,932,389, U.S. Pat. No. 3,054,741 and Netherlands Octooraanvrage No. 7,306,030.

#To a stirred suspension of 57% sodium hydride in mineral oil (1.3 g, 30.9 mmol) in tetrahydrofuran (THF) was added dropwise a solution of dimethyl (2-oxo-3-phenoxypropyl)phosphonate (coupling reagent) (8.4 g, 32.5 mmol) in THF. The mixture was stirred under nitrogen for 90 minutes then a solution of 2-[3 alpha-p-phenylbenzoyloxy-5 alpha-hydroxy-2 beta-formylcyclopent-1 alpha-yl]acetic acid, gamma-lactone (9.5 g, 27.1 mmol) in THF was added. After being stirred for 30 minutes, the reaction was quenched with acetic acid and concentrated. The residue was diluted with ethyl acetate, washed with water and brine, dried (MgSO.sub.4) and concentrated. Purification of the crude product by column chromatography using mixtures of ethyl acetate in benzene as eluents provided 9.5 g (72%) of the above titled Coupling Product (11a) as a white solid, mp 124.degree.-125.degree. C. after trituration with ether:IR (KBr) 1775, 1715, 1675, 1630, cm.sup.-1 (carbonyl groups) and 970 cm.sup.-1 (trans CH.dbd.CH).

#A heterogeneous mixture of the Coupling Product (11a) of Example 1 (5.74 g, 11.9 mmol) and 5% palladium on carbon (200 mg) in ethyl acetate (30 ml) and methanol (20 ml) was treated with 50 lbs of hydrogen in a Parr Shaker until hydrogen consumption ceased. The catalyst was collected by filtration and the filtrate concentrated to provide 5.71 g, (99%) of the above titled Reduction Product (21b) as a viscous, colorless oil which was used without further purification.

#A heterogeneous mixture of the Reduction Product (21b) of Example 2 (5.71 g, 11.9 mmol) and potassium carbonate (1.93 g, 14.0 mmol) in methanol (200 ml) and tetrahydrofuran (20 ml) was stirred at room temperature for 3.5 hours, then was acidified (pH 3) with 1N hydrochloric acid. The acidified mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (MgSO.sub.4) and concentrated. Purification of the residue by column chromatography using ether as an eluent afforded 1.79 g (50%) of the above titled Ketone (32) as a viscous oil.